Prostate cancer is the most common cause of non-cutaneous cancer in men and is a leading lethal malignancy with increasing incidence worldwide. The mortality rate of prostate cancer is decreasing steadily at approximately 4% yearly since 1994, while the incidence rate increases at slightly less than 2% yearly. Prostate cancer continues to have the highest incidence rate and the second highest mortality rate of any cancer for men in the US. In 2004 there were more than 230,000 new cases of prostate cancer in the US and 29,000 men died of the disease. As a group, cancer represents the second leading cause of death in men and considered alone, prostate cancer is in the top 10 overall causes of death for US men. Since the incidence of prostate cancer increases with age, the aging of the population is expected to result in an increased mortality due to prostate cancer in the future. Also, improved diagnostic techniques results in earlier diagnosis and many men are now treated while still physically and sexually active.
Current therapies for prostate cancer, including medical or surgical castration, have a significant impact on many aspects of quality of life. Non-steroidal oral antiandrogen therapy with flutamide (Eulexin™, Schering; Eulecin; Flutacan; Flutamid), bicalutamide (Casodex™, AstraZeneca) and nilutamide (Anandron™, Aventis) has demonstrated efficacy in several stages of prostate cancer and represents an alternative therapeutic strategy to castration. Survival data for men with previously untreated, locally advanced disease reveal that antiandrogen monotherapy provides survival benefits that do not differ significantly from castration. Unfortunately, systemic hormonal treatment also causes extensive side effects.
These data have stimulated research and exploration of alternative treatment methods and therapeutic agents by which current treatment regimens may be improved e.g. by local targeting as well as strategies focusing on delaying androgen independence and of influencing prostate cancer invasion. One way to provide a successful outcome of antiandrogen therapy, i.e. high efficacy and low probability for serious side effects, is to ensure local specific targeting of the therapeutic moiety at the tumor site, and thereby minimizing systemic effects.
Benign prostatic hyperplasia (BPH) can be detected histologically in more than 50% of 60 years old men and in about 90% of men 85 years old. Symptoms occur in a quarter of these men. With the current increase in the elderly population the number of cases of BPH is also increasing. According to the American Urological Association Guidelines on Management of BPH, transurethral resection of the prostate (TURP) is the most common surgical treatment for symptomatic BPH. However, the outcome is not always satisfactory for patients since hospitalization is required for TURP and there is a risk of various complications. Medical treatment, including [alpha]-1 blockers, is another possible choice for the management of BPH, but tolerance can occur in the long term. Minimally invasive therapy, positioned between medical treatment and radical surgery, has been introduced for BPH, but current methods require advanced technology and expensive devices.
The relationship between prostate inflammation and prostate cancer is increasingly becoming a focus of clinical and basic science research in urology. Reviews of epidemiologic and clinical research have suggested a link between chronic prostate inflammation and the development of prostate cancer. Evidence for the biologic plausibility of this association ranges from in vivo inflammatory models of prostate carcinogenesis to increased inflammatory mediators and markers of oxidative stress in the serum, urine, and tumors of patients with prostate cancer. Although the causal role of inflammation on prostate cancer is yet to be established, possible mechanisms include the generation of reactive oxygen species, induction of cyclooxygenase-2, and release of paracrine factors that may lead to the induction or proliferation of cancer. Prostate inflammation, particularly when associated with bacterial infection, is associated with an elevation of serum PSA levels.
The prostate is located anteriorly to the rectum. Above the prostate gland is the urinary bladder and below the urogenital diaphragm. The seminal vesicles form the ejaculatory ducts and enter the gland in a posterio-lateral direction and emerge in the urethra in approximately the middle of the gland. The gland is covered by a fibrotic capsule and has an elastic consistency. The function of the prostate gland is to secrete the milky substance of seminal fluid. Before puberty, this function does not exist and the gland is very small. Unlike many organs the growth of the prostate gland continues throughout the lifespan of a man, often resulting in a benign prostatic hyperplasia of the gland.
Pathology and Pathophysiology of Prostate Cancer
The histopathology of high-grade prostate intraepithelial neoplasia consists of architecturally benign prostate acini lined by cells that seem to be malignant. Prostates with carcinoma have more of these foci than those without carcinoma. Prostate glands with extensive high-grade prostate intraepithelial neoplasia also have more multifocal carcinomas. At the time of diagnosis a majority of patients have local prostate cancer disease without spread or metastases.
Locally advanced non-metastatic diseases include patients who have a disease penetrating through the prostate capsule or invading a seminal vesicle on digital rectal examination. The incidence of locally advanced disease varies from population to population and consists of patients who are either untouched by screening efforts or have an unusually aggressive natural history with a disease growing rapidly between screening intervals.
Androgens play an essential role in differentiation and growth of the male reproductive tract, pubertal maturation and development of secondary male sex characteristics, initiation and regulation of spermatogenesis, and male sexual behavior. Steroidal androgens increase muscle mass, bone mass, and strength; stimulate male pattern baldness; and alter serum lipid profiles and fat distribution. Testosterone, synthesized and secreted by the testes, and its more potent 5-reduced metabolite, dihydrotestosterone (DHT), are the principal biologically active endogenous androgens. Testosterone and dihydrotestosterone exert tissue-specific biological effects. For example, testosterone functions to stimulate muscle mass, sexual development, and spermatogenesis, whereas dihydrotestosterone plays critical roles in facial and body hair growth, acne, and prostate enlargement. The actions of both testosterone and dihydrotestosterone are mediated by the intracellular androgen receptor (AR), a member of the nuclear receptor superfamily of ligand-activated transcription factors. Upon binding of testosterone or dihydrotestosterone, androgen receptor undergoes a conformational change, binds to specific DNA sequences termed androgen response elements, forms complexes with nuclear coregulatory factors, and modulates the transcription of target genes.
Androgens are important in development and treatment of prostate cancer. Withdrawal of testosterone by surgical or medical castration is a well-known treatment for prostate cancer and is effective in 75-80% of patients with metastatic prostate cancer. In animals, testosterone and dihydrotestosterone have induced prostate cancer tumors, but the link between androgens and cancer development in man is less clear.
Treatment Options
Today the treatment options for early-stage prostate cancer can be grouped into four broad categories:                observation (“wait and see approach”),        surgery (radical prostatectomy),        radiotherapy (external-beam radiotherapy, brachytherapy or both),        hormone therapy.        
Especially elderly patients and those with co-morbidities may be observed without treatment. Surgery (radical prostatectomy) and radiotherapy (external-beam radiotherapy, brachytherapy or both) are the most widely accepted curative options for patients who need intervention.
Radical prostatectomy has been the standard against which other local treatments are compared. This procedure has been refined, resulting in high cure rates with decreased morbidity in appropriately selected patients. The reduction in morbidity has not resulted in reduced disease control.
External-beam radiotherapy involves daily treatment for 7-8 weeks. It has been studied extensively for early-stage prostate cancer, and like radical prostatectomy, has undergone a technological revolution, with results showing survival comparable to that of surgery, but with a different side-effect profile. Brachytherapy, which involves placement of radioactive sources directly into the prostate region of interest, is used in many centers. As a treatment for early-stage prostate cancer, it now achieves disease-free survival comparable with those of radical prostatectomy and external-beam radiotherapy. The advantage of brachytherapy is the dose escalation in the cancer without a dose escalation in the healthy tissue in the surroundings. All these local treatments have been refined, resulting in comparable cure rates; however, they all have various side-effect profiles.
Hormone therapy, although effective in the adjuvant setting for some patients with early-stage disease, can be used alone and as an alternative to observation. The prostate is a hormone-responsive organ, and this observation has been the basis for interventions for prostate cancer that either reduce serum testosterone or block the actions of this hormone.
Hormones have been used in combination with prostatectomy with limited success. However, hormones improve survival results when combined with radiotherapy, probably because of their different mechanisms of action. The hormonal therapy can independently destroy the prostate cancer and sensitize the tumor to radiation. The benefit of hormone therapy in addition to external-beam radiotherapy in intermediate-stage and locally advanced disease has been shown in many randomized studies. There seems to be particular improvement in selected patients with early-stage disease who have one or more poor prognostic factors (high-grade disease, high PSA (prostate specific antigen), or both), and if confirmed in outcome trials, hormone related therapy will probably be used much more in patients with early-stage disease in the future.
The most commonly used oral hormonal therapy today is bicalutamid (Casodex) and flutamide (Eulexin, Eulecin, Flutacan, Flutamid). The side effect spectrum of bicalutamid and flutamid, includes diarrhoea, breast enlargement, nausea, impotence, decreased libido, abdominal pain, flatulence, tiredness, asthenia, osteoporosis, sweating, hot flushes, loss of libido or erectile function, weight gain, gynaecomastia, and liver toxicity, and as a result a decreased quality of life. These side effects are to a major extent dose- and plasma/tissue concentration related, and thus dependent on high levels of the active drug in the systemic circulation and different tissues outside the prostate tissue. And, importantly, none of these side effects are related to or mediated by the local drug action in the prostate tissue. It is therefore reasonable to focus on novel therapeutic applications, which aim to improve the local concentration/amount versus time profile and increase the action of the anticancer agent in the prostate tissue.
Such an approach is valid since it has been reported that oral flutamide therapy acts via a suppression of the binding of the intraprostate dihydrotestosterone (active metabolite of testosterone) to the intracellular androgen receptor (AR).
Also many other methods for treating prostate diseases have been developed. Several are based on the intramuscular or subcutaneous application of sustained drug delivery formulations containing the active substance (such as gonadotropin hormone-releasing hormone (GnRH) agonists and GnRH antagonists). Also intraprostate (for instance antibiotics) and intralesional injection of active substances have been described. These methods have the disadvantages of producing either prolonged systemic exposure, or to require repetitive injections over substantial periods of time.
Accordingly, there is a need for developing novel methods for the treatment of prostate related diseases that lead to a more efficient treatment and at the same time make it possible to reduce the need for surgery and radio-treatments, and minimize the hormone related side-effects. To this end the present inventors have developed a method that involves local injection within the diseased prostate tissue of a controlled release composition of one or more active substances.
Such a site-specific drug delivery approach has numerous advantages in comparison to systemic pharmacological treatment methods in mammals for localized diseases. For instance, the incidence of a number of serious side effects is significantly lower and the drug will be delivered to the site of disease, i.e. the effect site, with a higher, less variable and more predictable local drug availability and effect. The daily dose that is given with a site-specific delivery composition is significantly lower than in systemic oral therapy. Hence, this site-specific drug delivery will result in reduced dose-related side effects, as the systemic concentration of the active drug(s) and its active metabolite(s) will be low, especially in comparison with corresponding oral drug therapy. It is not likely, that the low systemic concentration of the active drug will interact with other drugs in any way, i.e. no drug-drug interactions, nor any food-drug interactions are expected.